A series of amide and urea analogs I (R = Me, Et, cyclopropyl, furan-3-yl, Ph, NHBu, NMeOMe ,etc., R1 = H; R = Me, R1 = Me, cyclopentyl, PhCH2, etc.) based on the thiaplakortone A natural product scaffold were synthesized and screened for in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine- and mefloquine-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogs displayed potent inhibition of P. falciparum growth (IC50 <500 nM) and good selectivity for P. falciparum vs. human neonatal foreskin fibroblast cells (selectivity index >100). Two of these compds., I (R = Me, NHBu, R1 = H), exhibited good aq. soly. and metabolic stability, and when administered s.c. to mice (32 mg kg-1), plasma concns. remained above 0.2 μM for at least 8 h. Both I (R = Me, NHBu, R1 = H) were well tolerated in mice after s.c. administration of 32 mg kg-1 twice daily for 4 days. Using this regimen blood stage P. berghei was suppressed by 52% for I (R = Me, R1 = H) and 26% for I (R = NHBu, R1 = H), relative to the vehicle control.